Li Hongli, Xiao Qiao, Zhu Lemei, Kang Jin, Zhan Qiong, Peng Weijun
Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
National Clinical Research Center for Metabolic Diseases, Changsha, 410011, China.
J Pharm Anal. 2025 Apr;15(4):101106. doi: 10.1016/j.jpha.2024.101106. Epub 2024 Sep 19.
Alzheimer's disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both experiments with amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NOD-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D (gasdermin D (GSDMD)), and interleukin-18 (IL-18)) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2 (COX-2)-NLRP3 inflammasome-gasdermin D (GSDMD) axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
阿尔茨海默病（AD）是一种进行性痴呆，是最常见的神经退行性疾病之一。基于直接的淀粉样蛋白和tau免疫疗法的淀粉样β（Aβ）和tau调节剂的临床试验结果令人失望。目前尚无有效策略减缓AD的进展。在此，我们强调脂质代谢失调，尤其是神经酰胺（Cers）水平升高，是AD发病机制中一个关键但未得到充分探索的方面。我们的研究阐述了Cers在促进小胶质细胞焦亡中的作用，小胶质细胞焦亡是一种程序性细胞死亡形式，不同于凋亡和坏死性凋亡，其特征是细胞肿胀以及由NLRP3炎性小体途径介导的细胞膜破裂。利用淀粉样前体蛋白（APP）/早老素1（PS1）转基因小鼠实验和BV-2小胶质细胞检测，我们研究了Cers对小胶质细胞焦亡的激活作用以及具有已知抗氧化和抗炎特性的黄酮类化合物淫羊藿苷（ICA）对其的抑制作用。我们的研究结果显示，AD模型小鼠大脑中的Cers水平和焦亡标志物（NOD样受体家族含pyrin结构域3（NLRP3）、含半胱天冬酶募集结构域的凋亡相关斑点样蛋白、半胱天冬酶-1、gasdermin D（GSDMD）和白细胞介素-18（IL-18））显著增加，表明Cers通过诱导小胶质细胞焦亡直接参与AD病理过程。相反，ICA治疗有效降低了这些焦亡标志物和Cers水平，从而减轻了小胶质细胞焦亡，提示了一种针对AD的新型治疗作用机制。这项研究不仅增进了我们对Cers在AD中致病作用的理解，还将ICA引入作为AD治疗的一个有前景的候选药物，它能够通过环氧合酶-2（COX-2）-NLRP3炎性小体-gasdermin D（GSDMD）轴减轻神经炎症和焦亡。我们的结果为进一步探索神经退行性疾病中的Cer代谢紊乱铺平了道路，并突出了靶向AD中小胶质细胞焦亡的治疗潜力。
